This proposal describes a 5-year mentored research project that has the goal of exploring the relationship between disease-protective major histocompatibility complex (MHC)/human leukocyte antigen (HLA) genetic loci, gut commensal microbiota and autoimmune diabetes (T1D). This project will build upon the principal investigator's preliminary data and strong background in immunology and infectious diseases. The comprehensive career development plan combines a strong mentorship team with additional didactic and practical training in gnotobiotic, microbiologic and large data set analyti techniques, which will facilitate the PI's transition into a successful independent investigator. The proposed research will take place in the stimulating research environment of Harvard Medical School within the laboratory of Drs. Diane Mathis and Christophe Benoist. The mentor, Dr. Mathis, is a world-renowned immunologist who has successfully mentored many physician-scientists during her 30-year career. The research and career development of the primary investigator will benefit from the extensive scientific and mentorship resources available to him. The MHC and HLA loci possess the strongest genetic association with T1D, in mice and humans respectively. Some loci such as the MHC class II E molecule offer dominant protection from T1D, but the mechanisms for this protection remains poorly understood. Commensal microbiota also influences the development of the immune system and affects the risk for developing T1D. The goal of this proposal is to explore interactions between gut microbiota, the MHC/HLA loci and the development of T1D in the non-obese diabetic (NOD) strain of mice and its closely related but non-diabetic transgenic line, expressing the protective MHCII E molecule (E?.NOD). Our preliminary data indicate that antibiotic disruption of the gut microbiota induces insulitis in E?.NOD mice. We have also demonstrated maternal transfer of protection from insulitis and T1D from E?.NOD mothers to NOD pups, suggesting transfer of protective microbiota from mother to pup. Therefore, we hypothesize that the diabetes-protective effect of the E molecule reflects an impact on the gut microbiota, which has a secondary influence on the immune system. To explore this hypothesis, we will directly test whether E?.NOD mice possess different microbes than NOD mice, and whether transfer of these microbes protects NOD mice from T1D. We will further identify these protective microbes and identify immune system components in E?.NOD mice that correlate with protection from T1D. To test whether the HLA alleles behave similarly we will explore the microbiota and gut immune system of NOD mice expressing human disease protective or risk-associated HLA alleles in place of their MHC genes. Ultimately, these experiments will shed light on the relationship between MHC and HLA loci, commensal microbiota and autoimmune diabetes. Moreover, identification of immunomodulatory bacteria and their associated immune system targets offers the potential for novel therapies for T1D, and perhaps other autoimmune diseases.